VJToday

FDA approves zanidatamab-based combinations for first line HER2-positive locally advanced or metastatic GC, GEJ, and GEA

On August 25, 2026, the U.S. Food and Drug Administration (FDA) granted approval to zanidatamab–
based combinations in the first-line treatment of HER2-positive unresectable locally advanced or
metastatic gastric cancer (GC), gastroesophageal junction (GEJ), or esophageal adenocarcinoma (GEA).1 Although HER2-directed therapy such as trastuzumab has improved outcomes in HER2-positive GEA, overall survival in this setting remains poor, highlighting the need for more effective first-line approaches that can provide deeper and more durable disease control.2

The application is supported by findings from the Phase III HERIZON-GEA-01 trial (NCT05152147),
which evaluated zanidatamab, a dual HER2-targeted bispecific antibody, plus chemotherapy with or
without tislelizumab versus trastuzumab plus chemotherapy. The trial randomized 914 patients to
the three treatment groups, with progression-free survival (PFS) by blinded independent central
review and overall survival (OS) being the dual primary endpoints.3

Both zanidatamab-containing regimens significantly improved progression-free survival (PFS)
compared with trastuzumab plus chemotherapy. Median PFS was 12.4 in patients receiving
zanidatamab, tislelizumab, and chemotherapy, compared with 8.1 months for trastuzumab plus
chemotherapy (HR, 0.63, 95% CI: 0.51, 0.78). The triplet combination also demonstrated a significant
overall survival (OS) benefit, with median OS of 26.4 months versus 19.2 months with trastuzumab
plus chemotherapy (HR, 0.72, 95% CI: 0.57, 0.90). Additional OS analyses is planned for zanidatamab
and chemotherapy arm. No new safety signals were observed for zanidatamab or tislelizumab.3

Filippo Pietrantonio, MD, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, spoke with us
at ASCO GI 2026, commenting on the trial data, stating that:

“Of course we should be aware of the possibility of increased incidence of diarrhea with the use of
zanidatamab and this will require prophylactic treatment with loperamide and also close monitoring
of these class specific side effects. But in the clinical practice, I think it will be feasible and appropriate
for most patients, so we will be happy to treat our patients as soon as the agent will be available in
the clinical practice.”

These findings support zanidatamab-based combinations as a potential new first-line standard for
HER2-positive advanced GEA, offering clinically meaningful improvements in PFS and OS in a setting
where durable treatment benefit remains a significant unmet need.

References:

  1. U.S. Food and Drug Administration. FDA approves zanidatamab-hrii and tislelizumab-jsgr for HER2-positive gastric, gastroesophageal junction, or esophageal adenocarcinoma. Available here. (Last Accessed 25/08/2026).
  2. Kawakami T, Yamazaki K. Recent progress in treatment for HER2-positive advanced gastric cancer. Cancers. 2024 Apr 30;16(9):1747. doi:10.3390/cancers16091747
  3. Elimova E, Rha SY, Shitara K, Liu T, Tabernero J, Lee K-W, et al. Zanidatamab + chemotherapy (CT) ± tislelizumab for first-line (1L) HER2-positive (HER2+) locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma (mGEA): Primary analysis from HERIZON-GEA-01. J Clin Oncol 2026;44(2_suppl)